Clinical mesenchymal stem cell therapy in ischemic cardiomyopathy

Central MessageDespite encouraging preclinical studies, the early promise of mesenchymal stem cell therapy has yet to be fulfilled in clinical trials of patients with ischemic cardiomyopathy.See Commentaries on pages 142 and 144. Despite encouraging preclinical studies, the early promise of mesenchymal stem cell therapy has yet to be fulfilled in clinical trials of patients with ischemic cardiomyopathy. See Commentaries on pages 142 and 144. Feature Editor's Introduction—Nearly 20 years ago, experimental reports of myocardial repair and regeneration with bone marrow-derived stem cells began to appear in the literature. The hypothesis that adult hearts had capacity for regeneration was contrary to prior science and generated intense interest in both research and clinical communities. This led to early clinical trials evaluating the safety and efficacy of various types of stem cells for the treatment of ischemic cardiomyopathy. Some researchers in the field believed that translation of experimental work into the clinical realm occurred rapidly and impulsively. As these trials progressed, 1 by 1 the experimental reports of myocardial regeneration were refuted, and a new hypothesis—that stem cell treatment improves cardiac function through a paracrine effect—was born. The result is a sobering tale of how early acceptance of shaky experimental data can impede scientific progress for years. Dr Yau and colleagues critically evaluate the clinical trial data on mesenchymal stem cell therapy in humans with ischemic cardiomyopathy. They identify several reasons why the results of trials have been inconsistent and propose important ways in which we can better evaluate the efficacy of this therapy in the future.Leora B. Balsam, MD Chronic heart failure affects an estimated 26 million people worldwide and is the leading cause of hospitalization in North America and Europe.1Ambrosy A.P. Fonarow G.C. Butler J. Chioncel O. Greene S.J. Vaduganathan M. et al.The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries.J Am Coll Cardiol. 2014; 63: 1123-1133Crossref PubMed Scopus (1096) Google Scholar Ischemic heart disease is the most common cause of heart failure.2Gheorghiade M. Sopko G. De Luca L. Velazquez E.J. Parker J.D. Binkley P.F. et al.Navigating the crossroads of coronary artery disease and heart failure.Circulation. 2006; 114: 1202-1213Crossref PubMed Scopus (241) Google Scholar Although advances in early reperfusion therapy have significantly reduced the early mortality associated with myocardial infarction, many patients develop heart failure secondary to the ventricular remodeling after an acute coronary event. Advances in guideline-directed medical therapy, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, mineralocorticoid receptor blockers, and angiotensin receptor neprilysin inhibitors, have substantially reduced the mortality associated with chronic heart failure.3Burnett H. Earley A. Voors A.A. Senni M. McMurray J.J. Deschaseaux C. et al.Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction: a network meta-analysis.Circ Heart Fail. 2017; 10: e003529Crossref PubMed Scopus (103) Google Scholar Nonetheless, this condition carries considerable morbidity and mortality because current medical therapies mitigate adverse ventricular remodeling but do not repair the underlying damage caused by the loss of cardiomyocytes. Thus, there remains an unmet need for novel therapies that durably restore ventricular function in patients with chronic ischemic cardiomyopathy (ICM). In recent years, stem cell therapy for cardiac regeneration has emerged as a promising therapeutic avenue. Among various candidate cell types, mesenchymal stem cells (MSCs) have garnered particular interest due to their ease of procurement, extensive proliferation in vitro, and broad immunomodulatory and anti-inflammatory properties. These stromal cells are found in a variety of tissues and are loosely defined as CD105+CD73+CD90+/CD45−CD34−CD14−CD19- cells that are plastic-adherent when cultured in vitro and can differentiate into osteoblasts, adipocytes, and chondroblasts.4Dominici M. Le Blanc K. Mueller I. Slaper-Cortenbach I. Marini F. Krause D. et al.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317Abstract Full Text Full Text PDF PubMed Scopus (11171) Google Scholar Over the past 2 decades, MSCs have been extensively evaluated to treat various cardiac conditions in both preclinical and clinical studies. Herein, we review the clinical evidence surrounding MSC use in the treatment of ICM. Although a detailed analysis of the preclinical studies of MSC therapy for ICM is beyond the scope of this review, it is worth mentioning that these cells have been extensively studied in small and large animal models, using multiple cell sources (eg, allogeneic vs autologous and bone marrow- vs adipose tissue-derived) and routes of administration (eg, direct transepicardial injection, transendocardial, intracoronary, and intravenous).5Pittenger M.F. Discher D.E. Peault B.M. Phinney D.G. Hare J.M. Caplan A.I. Mesenchymal stem cell perspective: cell biology to clinical progress.NPJ Regen Med. 2019; 4: 22Crossref PubMed Scopus (410) Google Scholar Collectively, these preclinical studies have demonstrated that MSC therapy is effective at reducing scar size and improving left ventricular (LV) ejection fraction (LVEF) after myocardial infarction. A meta-analysis of 52 preclinical large animal studies showed that cell therapy is associated with a moderate 7.5% improvement in LVEF in animals with ICM.6van der Spoel T.I. Jansen of Lorkeers S.J. Agostoni P. van Belle E. Gyöngyösi M. Sluijter J.P. et al.Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease.Cardiovasc Res. 2011; 91: 649-658Crossref PubMed Scopus (174) Google Scholar Furthermore, this study demonstrated that MSCs from any source (ie, bone marrow, adipose tissue, or umbilical cord) were more effective at improving LVEF compared with bone marrow-derived mononuclear cells (BMCs). Early theories that MSCs engraft in the myocardium and replace damaged cardiomyocytes have been refuted.7Toma C. Pittenger M.F. Cahill K.S. Byrne B.J. Kessler P.D. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart.Circulation. 2002; 105: 93-98Crossref PubMed Scopus (1947) Google Scholar,8Grinnemo K.H. Mansson-Broberg A. Leblanc K. Månsson-Broberg A. Leblanc K. Corbascio M. et al.Human mesenchymal stem cells do not differentiate into cardiomyocytes in a cardiac ischemic xenomodel.Ann Med. 2006; 38: 144-153Crossref PubMed Scopus (58) Google Scholar A hypothesis that the heart itself contains a population of c-Kit + stem cells that are stimulated by MSCs to differentiate into cardiomyocytes has also been disproven.9Chien K.R. Frisen J. Fritsche-Danielson R. Melton D.A. Murry C.E. Weissman I.L. Regenerating the field of cardiovascular cell therapy.Nat Biotechnol. 2019; 37: 232-237Crossref PubMed Scopus (71) Google Scholar The alternative—and now widely accepted—explanation for the beneficial effects of MSCs on cardiac function is the paracrine hypothesis, which stipulates that MSCs secrete poorly characterized paracrine factors with antifibrotic and proangiogenic effects on injured heart tissue.10Gnecchi M. He H. Liang O.D. Melo L.G. Morello F. Mu H. et al.Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells.Nat Med. 2005; 11: 367-368Crossref PubMed Scopus (1297) Google Scholar,11Kinnaird T. Stabile E. Burnett M.S. Shou M. Lee C.W. Barr S. et al.Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms.Circulation. 2004; 109: 1543-1549Crossref PubMed Scopus (1090) Google Scholar To test this hypothesis, the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery trial delivered autologous MSCs to akinetic and hypokinetic myocardium unsuitable for revascularization in 6 patients.12Karantalis V. DiFede D.L. Gerstenblith G. Pham S. Symes J. Zambrano J.P. et al.Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial.Circ Res. 2014; 114: 1302-1310Crossref PubMed Scopus (234) Google Scholar A reduction in scar size and modest improvements in tissue perfusion were observed in the MSC-treated patients, as assessed by magnetic resonance imaging (MRI). However, given the small sample size and lack of a placebo group, these findings remained hypothesis-generating. On the basis of these preclinical and mechanistic studies, several randomized clinical trials of MSC therapy for ICM have been conducted. These trials consist of small Phase 1 and 2 studies, with no successful Phase 3 trials of MSC therapy for ICM reported to date. Below, we summarize the findings from some landmark trials before offering a broad perspective on the totality of the available evidence (Table 1).Table 1Summary of landmark clinical trials on mesenchymal stem cell (MSC) therapy in patients with ischemic cardiomyopathy (ICM)StudyStudy designPopulationIntervention vs comparisonOutcomesPOSEIDON (2012)Randomized, nonplacebo controlled30 patients with ICM and left ventricular dysfunction3 doses of transendocardial allogenic vs autologous MSCs (20, 100, 200 million cells)•No difference in SAEs∗SAEs included death, nonfatal myocardial infarction, stroke, heart failure hospitalization, cardiac perforation, tamponade, or sustained ventricular arrhythmia., infarct size, LV sphericity index, LVEF in allogenic vs autologous MSC•Autologous MSC: modest improvement in 6-min walk test and QOL•20 million cells yielded better LVESV and LVEF vs 200 million cellsTAC-HFT (2014)Randomized, placebo controlled65 patients with ICM and LVEF <50%Transendocardial autologous MSCs or BMCs vs placebo•No difference in SAEs, LV volume, or LVEF•Improved 6-min walk test and infarct size only with MSC•Better QOL with MSC or BMC, but not placeboPRECISE (2014)Randomized, placebo controlled27 patients with ICMTransendocardial adipose derived MSCs vs placebo•No difference in major adverse cardiac or cerebral events, LVEF, LV volumes•Modest improvement in LV mass and wall motion score index only in MSC•Decline in metabolic equivalents and maximum oxygen consumption only in placeboMSC-HF (2015, 2020)Randomized, placebo controlled60 patients with ICM, NYHA functional class II-III, LVEF <45%Intramyocardial autologous bone derived MSCs vs placebo•At 6 mo, reduced LVESV and improved LVEF, stroke volume, cardiac output, myocardial mass only in MSC group; but no difference in NYHA functional class, 6-min walk test, or QOL•At 1 y, improved LVEF, stroke volume, myocardial mass, and QOL and fewer angina hospitalizations at 4 y only in MSC groupRIMECARD (2017)Randomized, placebo controlled21 patients with ICM and reduced LVEF and 9 patients without ICMIntravenous allogeneic umbilical cord derived MSC vs placebo•No difference in adverse events, mortality, heart failure hospitalization, maximum oxygen consumption, metabolic equivalents, exercise tolerance between groups•Improvement in LVEF, NYHA functional class, and QOL only in MSCLVAD MPC2 (2019)Randomized, placebo controlled159 patients with end-stage heart failure due to ICM (44%) or non-ICM (56%), undergoing LVAD implantation150 million mesenchymal progenitor cells vs placebo•No safety end point events in either group (myocarditis, myocardial rupture, neoplasms, hypersensitivity and difference in to from Stem Cell on adverse left LVEF, left ventricular ejection of left ventricular end in Ischemic Heart BMC, bone marrow-derived mononuclear Randomized of Stem in of Ischemic Mesenchymal Cell Therapy in Heart Heart Randomized of Mesenchymal Stem on LVAD of of Mesenchymal on in LVAD left ventricular included death, nonfatal myocardial infarction, stroke, heart failure hospitalization, cardiac perforation, tamponade, or sustained ventricular in a new Stem Cell on adverse left LVEF, left ventricular ejection of left ventricular end in Ischemic Heart BMC, bone marrow-derived mononuclear Randomized of Stem in of Ischemic Mesenchymal Cell Therapy in Heart Heart Randomized of Mesenchymal Stem on LVAD of of Mesenchymal on in LVAD left ventricular The Stem Cell on J.M. Gerstenblith G. DiFede Velazquez D.L. Zambrano J.P. et of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial in patients with ischemic the randomized PubMed Scopus Google Scholar was a Phase 1 and nonplacebo of transendocardial allogenic autologous MSCs in patients with ICM and LV doses and 200 million were The end point was a of adverse events death, nonfatal myocardial infarction, stroke, hospitalization for heart cardiac perforation, tamponade, or sustained ventricular occurred in 1 group in patients in the allogeneic group, and in patients in the autologous group 1 secondary end both showed a reduction in infarct size and LV sphericity index compared with but no improvement in but not allogeneic MSC therapy in modest improvements in the walk test and of in LV and in LVEF were in patients 20 million 200 million an due to MSC at a need for an of cells to cell reduced cell with J.M. D. of stem cells for ischemic PubMed Scopus Google Scholar in Ischemic Heart DiFede D.L. Zambrano J.P. V. et mesenchymal stem cells and mononuclear bone cells for ischemic the randomized 2014; PubMed Scopus Google Scholar was a Phase 1 and 2 study of patients with ICM and LVEF transendocardial autologous MSCs BMCs or placebo an as at The of was for the MSC and and for 1 QOL improved with both MSCs and BMCs compared with However, walk test results and infarct size improved only with LV and LVEF were in The of Stem in of Ischemic R. J. R. et cells in patients with ischemic the Heart J. 2014; PubMed Scopus Google Scholar was the trial to the safety and of administered MSCs in patients with ICM. In MSC-treated and 6 patients, no were observed with cell or the of major adverse cardiac or cerebral events was between the in the group and in the treatment On LVEF and LV were in the MSC group compared with their or the On there were modest improvements in LV mass and wall motion score index only with equivalents and maximum oxygen consumption were in the MSC group, but significantly The Mesenchymal Cell Therapy in Heart A.A. E. S. A. et marrow-derived mesenchymal stromal cell treatment in patients with ischaemic heart failure: a randomized trial Heart J. PubMed Scopus Google Scholar was Phase trial the effects of administered autologous bone marrow-derived MSCs in patients with ICM. patients to years with ischemic heart Heart functional class II or and LVEF were randomized to MSC treatment or The end point was in LVESV at 6 by or 6 LVESV was reduced compared with in the MSC group and in the placebo with there were also improvements in LVEF, stroke volume, cardiac output, and myocardial mass in MSC-treated In to these imaging no were observed in NYHA class, walk test, and QOL score between the of were not between the treatment in and in 20 a MSC-treated patients showed improved LVEF, stroke volume, myocardial mass, scar tissue, and QOL score at as as reduced hospitalizations for angina at 4 A.A. E. S. M. et marrow-derived mesenchymal stromal cell treatment in patients with ischaemic heart failure: of the Heart Fail. PubMed Scopus Google Scholar the a was in that patients with the of MSCs improvement in of Mesenchymal Stem on J. E. C. et and efficacy of the of umbilical cord mesenchymal stem cells in patients with heart failure: a randomized trial trial clinical trial of umbilical cord mesenchymal stem cells on Res. 2017; PubMed Scopus Google Scholar was the clinical trial to evaluate the safety and efficacy of of allogeneic umbilical MSCs in patients with heart failure and reduced This Phase 1 and trial was in 2 in and randomized patients with ischemic of or cardiomyopathy. adverse events to cell were MSC-treated patients showed improvement in LVEF at and as as in NYHA functional class and QOL were observed between in mortality, heart failure maximum oxygen consumption, metabolic equivalents, or exercise a of adverse events occurred in patients in the treatment group adverse events in patients in the The LVAD MPC2 of of Mesenchymal on in LVAD A. et of mesenchymal cells and successful from left ventricular in patients with heart failure: a randomized clinical 2019; PubMed Scopus Google Scholar patients with end-stage heart failure due to ICM (44%) or cardiomyopathy undergoing LVAD Patients were randomized to million mesenchymal progenitor cells of or a safety end point (myocarditis, myocardial rupture, hypersensitivity or The efficacy to a from LVAD not in the trial population between patients and but in patients with ICM, in be to have are of Phase 1 and 2 clinical trials of MSC therapy in patients with ICM have that in patients with chronic ICM and reduced LVEF, MSCs LV function and clinical C. A. E. Stem cell therapy for chronic ischaemic heart disease and heart Google Scholar However, be in of the of evidence and the of the studies, including small multiple of secondary end and of trials (eg, in sources of MSCs and types of cells of and As detailed in the MSC trials have inconsistent and on cardiac function, and no on clinical as mortality or for heart Furthermore, it has been that studies with the most have reported the most effects of MSC therapy on M. M. S. et in autologous bone stem cell trials and of ejection fraction and 2014; PubMed Scopus Google Scholar the that a lack of have generated a the functional of In of the of Phase 1 and 2 clinical Phase 3 trials using current of MSC many of patients to clinical that a Thus, there remains a need to develop to the of In the we review that are for MSC therapy is This of the of MSCs before injection, either through the use of to the or by their for through the use of or H. I. M. P. by mesenchymal stem 2017; PubMed Scopus Google H. Mesenchymal stem cell and current and Cell 8: PubMed Scopus Google Scholar Although promising in preclinical studies, clinical trial results of this have been in the autologous MSCs not exercise capacity in patients with chronic ischemic heart disease compared with A.A. E. S. et stromal cells for treatment of patients with chronic ischemic heart disease a randomized 2017; PubMed Scopus Google Scholar the and of for of Ischemic Heart trial was a study in patients with ischemic heart J. A. S. B. et cell therapy for ischaemic heart failure: results at of the clinical Heart J. 2017; 38: Google Scholar Patients were randomized to autologous bone marrow-derived MSCs or The MSCs were with a bone and J. A. D. M. M. J. et stem cell therapy in heart failure: the stem Cell therapy in heart randomized trial with Am Coll Cardiol. PubMed Scopus Google Scholar the end of mortality, heart with Heart walk and between the MSC and placebo In MSC-treated patients had LV end and LVESV at M. J. A. et of mesenchymal stem cell therapy on left ventricular results from the heart failure therapy Heart Fail. 2017; PubMed Scopus Google Scholar and fewer end point events in a of patients with LV end at J. A. S. B. et cell therapy for ischaemic heart failure: results at of the clinical Heart J. 2017; 38: Google Scholar However, these were not and be promising is MSCs with cell types (eg, cells and to their A clinical of this is the for Patients Heart a Phase 2 trial in which patients with ischemic heart failure were randomized to of autologous bone marrow-derived MSCs and A.A. C. et for patients with ischaemic heart failure: a Full Text Full Text PDF PubMed Scopus Google Scholar The study patients in North The end point was a of mortality, cardiovascular to and to treat acute heart In a there was a reduction in the end point in the treatment group, the clinical trials a clinical of MSC therapy in patients with ICM. the trial not a MSC or group, the of cell types their be clinical trials of MSC therapy for ICM have on direct or for cell These of cell and which treatment To this many have cell by to the cells using tissue Some preclinical studies have that the effects of MSC therapy can be by the cells on tissue before Lee et in using cell of autologous bone marrow-derived mesenchymal stem cells for in a PubMed Scopus Google Scholar MSCs have efficacy compared with direct of M. K. M. R. et of the heart with mesenchymal stromal cells for the treatment of heart PubMed Scopus Google Scholar remains to be these into improved in clinical studies. In to the several the to MSC therapy is the source tissue for most studies to have bone marrow- and adipose the umbilical cord and are also sources of M.F. Discher D.E. Peault B.M. Phinney D.G. Hare J.M. Caplan A.I. Mesenchymal stem cell perspective: cell biology to clinical progress.NPJ Regen Med. 2019; 4: 22Crossref PubMed Scopus (410) Google Scholar the tissue of MSC treatment remains to be MSCs can be derived in large from autologous or allogeneic M.F. Discher D.E. Peault B.M. Phinney D.G. Hare J.M. Caplan A.I. Mesenchymal stem cell perspective: cell biology to clinical progress.NPJ Regen Med. 2019; 4: 22Crossref PubMed Scopus (410) Google Scholar studies have compared the of autologous allogeneic MSC J.M. Gerstenblith G. DiFede Velazquez D.L. Zambrano J.P. et of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial in patients with ischemic the randomized PubMed Scopus Google Scholar Furthermore, several studies have demonstrated and of MSCs with that cell for allogeneic and into be from autologous therapies with patients with without some treatment of the M.F. Discher D.E. Peault B.M. Phinney D.G. Hare J.M. Caplan A.I. Mesenchymal stem cell perspective: cell biology to clinical progress.NPJ Regen Med. 2019; 4: 22Crossref PubMed Scopus (410) Google Scholar the MSC is with some studies with J.M. Gerstenblith G. DiFede Velazquez D.L. Zambrano J.P. et of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial in patients with ischemic the randomized PubMed Scopus Google Scholar and doses for therapeutic V. DiFede D.L. J. M. et study of allogeneic mesenchymal stem cells in patients with ischemic cardiomyopathy Res. 2017; PubMed Scopus Google Scholar most clinical studies to have on a of preclinical evidence that doses are M. A. et doses of cardiac mesenchymal cells are to a in with myocardial Cardiol. 2017; PubMed Scopus Google Scholar This is the of an clinical the of on in Patients Chronic Heart study MSCs can be delivered through a of transendocardial direct myocardial or The be by of cells from ischemic due to coronary C. J. Hare J.M. of delivery the efficacy of mesenchymal stem cell therapy for myocardial a meta-analysis of preclinical studies and clinical Res. 2017; PubMed Scopus Google Scholar The of MSCs be by the of (eg, infarct or scar The clinical of MSC therapy be due to MSC to or cell loss by tissue and MSC remains various tissue ways to the MSC and The early promise of MSC therapy for ICM remains to some Despite improvements in or in MSC-treated patients, clinical in Phase 3 trials have in QOL and reduced compared with observed in preclinical studies. As a MSC therapy has yet to the clinical realm in any and no has use in ICM. Despite in the an of stem cell to stem cell therapy to patients with heart A of treatment stem cells for patients with heart Med. 2017; PubMed Scopus Google Scholar are to these which to damage the in the field of stem cell

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